Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange
Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange
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DOI：
10.1073/pnas.1315798111
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发表时间：
2014-03-04
影响因子：
11.1
通讯作者：
Fesik, Stephen W.
中科院分区：
文献类型：
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作者：
Burns, Michael C.;Sun, Qi;Fesik, Stephen W.
致癌突变或组成型活性上游受体酪氨酸激酶导致小GT3 Ras的异常激活导致约30%的人类癌症中控制生长和存活的细胞信号失调。然而，Ras的有效抑制剂的发现一直难以实现。在这里，我们报告的小分子的识别，结合到一个独特的口袋上的Ras：Son of Sevenless（SOS）：Ras复合物，增加SOS催化的核苷酸交换率在体外，并调节细胞中的Ras信号通路。Ras的X射线晶体学：紧急呼救：与这些分子复合的Ras揭示了化合物结合在SOS的CDC 25结构域中的疏水口袋中，该疏水口袋邻近Ras的开关II区域。这些化合物所表现出的结构-活性关系可以根据多个X-射线共晶结构来合理化。突变分析证实了该结合位点的功能相关性，并显示其对化合物活性至关重要。这些分子在低微摩尔浓度下增加Ras-GTP水平并破坏细胞中的MAPK和PI 3 K信号传导。这些小分子代表了研究Ras急性激活的工具，并突出了SOS上的一个口袋，可以用来调节Ras信号传导。
Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in similar to 30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. Here, we report the identification of small molecules that bind to a unique pocket on the Ras: Son of Sevenless (SOS): Ras complex, increase the rate of SOS-catalyzed nucleotide exchange in vitro, and modulate Ras signaling pathways in cells. X-ray crystallography of Ras: SOS: Ras in complex with these molecules reveals that the compounds bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of multiple X-ray cocrystal structures. Mutational analyses confirmed the functional relevance of this binding site and showed it to be essential for compound activity. These molecules increase Ras-GTP levels and disrupt MAPK and PI3K signaling in cells at low micromolar concentrations. These small molecules represent tools to study the acute activation of Ras and highlight a pocket on SOS that may be exploited to modulate Ras signaling.